The present invention relates to novel tetracyclic amines and derivatives thereof useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The compounds of the present invention are useful in the treatment of neurodegenerative disorders including cerebrovascular disorders.
Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this degeneration is in part mediated by the excitotoxic actions of glutamate and aspartate at the N-methyl-D-aspartate (NMDA) receptor. This excitotoxic action is responsible for the loss of neurons in cerebrovascular disorders such as: cerebral ischemia or cerebral infraction resulting from a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery and cerebral trauma.
There are no specific therapies for these neurodegenerative diseases, however, compounds which act specifically as antagonists of the NMDA receptor complex, either competitively or noncompetitively, offer a novel therapeutic approach to these disorders: R. Schwarcz and B. Meldrum, The Lancet 140 (1985); B. Meldrum in "Neurotoxins and Their Pharmacological Implications" edited by P. Jenner, Raven Press, New York (1987); D. W. Choi, Neuron 1:623 (1988). Confirmation of the protective effects of noncompetitive NMDA antagonists in various pharmacological models of neurodegenerative disorders have appeared in the literature: J. W. McDonald, F. S. Silverstein, and M. V. Johnston, Eur. J. Pharmocol. 140:359 (1987); R. Gill, A. C. Foster, and G. N. Woodruff, J. Neurosci. 7:3343 (1987); S. M. Rothman, J. H. Thurston, R. E. Hauhart, G. D. Clark, and J. S. Soloman, Neurosci. 21:673 (1987); M. P. Goldbert, P-C. Pham, and D. W. Choi, Neurosci. Lett. 80:11 (1987); L. F. Copeland, P. A. Boxer, and F. W. Marcoux, Soc. Neurosci. Abstr. 14 (part1):420 (1988); J. A. Kemp, A. C. Foster, R. Gill, and G. N. Woodruff, TIPS 8:414 (1987); R. Gill, A. C. Foster, and G. N. Woodruff J. Neurosci. 25:847 (1988); C. K. Park, D. G. Nehls, D. I. Graham, G. M. Teasdale, and J. M. McCulloch, Ann. Neurol. 24:543 ( 1988); G. K. Steinburg, C. P. George, R. DeLaPlaz, D. K. Shibata, and T. Gross, Stroke 19:1112 (1988); J. F. Church, S. Zeman, and D. Lodge, Anesthesiology 69:702 (1988).
European Patent Application 230,370 discloses certain 5 substituted-10,11-dihydro-5H-dibenzocyclohepten-5,10 imines and analogues thereof useful for preventing or treating neurodegenerative disorders. The further preparation of these compounds is described by W. J. Thompson et al in J. Med. Chem. 33, 789 (1990) and K. C. Rice et al in J. Med. Chem. 33, 1069 (1990) The preparation of certain polyhydro derivatives of 10,11-dihydro-5H-benzo(a,d)cyclohepten-5,10-imines and their evaluation as N-methyl-D-aspartate antagonists are disclosed in European Patent Application 303,421, U.S. Pat. Nos. 4,869,791, 4,870,079, and 4,870,080 and by T. A. Lyle et al in J. Med. Chem. 33, 1047 (1990). The syntheses and reactions of N-methyl-15-aza-des-N-morphinan are described by K. Harasawa in Yakugaku Zasshi 77, 168 (1957), Yakugaku Zasshi 77 794 (1957) and Chem. Pharm. Bull. 3 369 (1955). The optical resolution of N-methyl-15-aza-des-N-morphinan and description of its analgesic activity is described by K. Harasawa in Yakugaku Zasshi 77, 172 (1957). However, none of the aforementioned publications teaches nor suggests the compounds of the present invention.